Novel TFAP2B mutations that cause Char syndrome provide a genotype-phenotype correlation

Feng Zhao, Constance G. Weismann, Masahiko Satoda, Mary Ella M. Pierpont, Elizabeth Sweeney, Elizabeth M. Thompson, Bruce D. Gelb

Research output: Contribution to journalArticlepeer-review

100 Scopus citations


To elucidate further the role, in normal development and in disease pathogenesis, of TFAP2B, a transcription factor expressed in neuroectoderm, we studied eight patients with Char syndrome and their families. Four novel mutations were identified, three residing in the basic domain, which is responsible for DNA binding, and a fourth affecting a conserved PY motif in the transactivation domain. Functional analyses of the four mutants disclosed that two, R225C and R225S, failed to bind target sequence in vitro and that all four had dominant negative effects when expressed in eukaryotic cells. Our present findings, combined with data about two previously identified TFAP2B mutations, show that dominant negative effects consistently appear to be involved in the etiology of Char syndrome. Affected individuals in the family with the PY motif mutation, P62R, had a high prevalence of patent ductus arteriosus but had only mild abnormalities of facial features and no apparent hand anomalies, a phenotype different from that associated with the five basic domain mutations. This genotype-phenotype correlation supports the existence of TFAP2 coactivators that have tissue specificity and are important for ductal development but less critical for craniofacial and limb development.

Original languageEnglish (US)
Pages (from-to)695-703
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number4
StatePublished - 2001
Externally publishedYes

Bibliographical note

Funding Information:
The authors wish to thank the patients with Char syndrome and their families, for their participation in the present study, Drs. Heather Waddy and Eric Haan, for their clinical assessments of the Australian kindred, and Pamela Mitchell, for her insights. This work was supported by National Institutes of Health grant HD38018 and March of Dimes grant FY00-246 (both to B.D.G.).


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